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Abstract

Sjögren’s syndrom (SS) is an autoimmune, chronic inflammatory disorder predominantly
affecting the salivary and lacrimal glands. The overall aim of this study was to determine
clinicopathological features in human and murine disease with regard to organization of
ectopic lymphoid tissue, and to explore possible strategies for detection of patients at
increased risk for extra-glandular manifestations.
Mononuclear cell infiltrates in the shape of germinal centers (GC) were observed in the
salivary glands of approximately 1/4th of patients. Phenotypic markers for GC components
such as T and B cells, proliferating cells, follicular dendritic cells and plasma cells confirmed
the ectopic GC formation. The pattern and distribution of homing and retentive chemokines
CXCL12, CXCL13 and CCL21, and adhesion molecules/integrin pairs ICAM/LFA and
VCAM/VLA, was described in various lymphoid organizations in minor salivary glands. In
addition, local autoantibody production was detected and correlated with serum levels.
Focal infiltrates and GC could be observed within the same gland, and were separated by
altered B and T cell ratios, higher degree of proliferation and the localization of plasma cells
in the periphery of infiltrates. Serum levels of BAFF and APRIL were elevated in pSS, and
were in part linked to focus score, elevated serum IgG and autoantibody levels.
In a large cohort of pSS, ectopic GC were also associated with higher focus scores, lower
mean un-stimulated salivary secretion, Ro/SSA and La/SSB autoantibodies, elevated RF-titres
and increased serum IgG. Not all morphological GC could be confirmed by
CD21/CD23/CD35 labeling, but clinical features remained comparable.
E-cadherin, an adhesion molecule important for epithelial tissue integrity, was investigated in
minor salivary glands. E-cadherin is the ligand of integrin αEβ7/CD103 and lymphocytes
expressing this integrin were increased in SS compared to non-SS. E-cadherin+ infiltrating
cells were identified as CD68+ macrophages. Serum levels of sE-cadherin were increased in
pSS compared to healthy blood donors and most likely mirror the chronic inflammatory state.
The non-obese diabetic (NOD) mouse is an animal model of SS. We observed significant
changes in inflammation between 8 and 17 weeks of age, while hyposalivation was first
observed between 17 and 24 weeks. In 1/3rd of mice older than 17 weeks, proliferating cells
were observed in the focal infiltrates. Significant differences were detected in serum cytokine
levels of IL-2, IL-5 and GM-CSF, and IL-4 and TNF-α in saliva. Salivary secretion correlated
with IL-4, IFN-γ and TNF-α levels in saliva of NOD mice, but not with inflammatory
changes in the salivary glands. Focal sialadenitis preceded hyposalivation, which occurred
without a significant change in inflammation in NOD mice. Proliferating inflammatory cells
indicate contribution of local factors in progression of SS-like disease.
In conclusion, ectopic germinal centers occur in a sub-group of patients with SS and are
characterized by autoantibody production, progressive disease and increased serum IgG. It
remains unclear whether the observed GC are a result of long-standing inflammation or
indeed have functional properties and thus play an active role in the pathogenesis. A future
challenge will be to identify and target trafficking molecules which drive the chronic
inflammation in SS, without affecting migration and function of leukocytes required for
protective immunity.